Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non–Small Cell Lung Cancer

Abstract

IMPORTANCECheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.OBJECTIVE To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. DESIGN, SETTING, AND PARTICIPANTSThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.INTERVENTIONS Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. MAIN OUTCOMES AND MEASURESThe primary end points, assessed in patients with Ն25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.

Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?

“…Blood based cfDNA offers a more convenient approach to assess TMB and potentially overcome the problem of tumor heterogeneity, but fewer clinical studies have validated this approach. In the B-F1RST and MYSTIC trials, blood-based TMB predicted response to immune checkpoint inhibitors in the first-line treatment of NSCLC (13,14). However, the relationship between TMB scores in tissue and blood remains unclear.…”

Subunits of ARID1 serve as novel biomarkers for the sensitivity to immune checkpoint inhibitors and prognosis of advanced non-small cell lung cancer.

“…On the contrary, mutations of ARID1A, which belongs to the ARID1 family member, might be associated with a different outcome among patients received ICIs treatment and participate to the improved ICIs outcome in NSCLC via associating KRAS mutations as reported by Gandara D, et al Besides, Goswami S, et al con rmed that ARID1A mutations plus CXCL13 expression as combinatorial biomarkers to predict the sensitive phenotype to ICIs in metastatic urothelial carcinoma [30]. In addition, the NGS examination based on MYSTIC trial [31] revealed that ARID1A mutations are associated with improved outcomes with the PD-1 inhibitor durvalumab plus the CTLA4 inhibitor tremelimumab reported by Rizvi NA, et al Based on these studies for new biomarkers of cancer immunotherapy especially for ARID1A mutations, we conducted our research in order to further investigate the signi cance of ARID1 mutations, including ARID1A and ARID1B, in predicting the prognosis of ICIs treatment for advanced NSCLC.…”

Nivolumab monotherapy or combination therapy with Ipilimumab for lung cancer: A meta-analysis of randomized controlled trials

“…The MYSTIC [26] trial is a phase III trial of patients with lung cancer that uses the same strategy but different drugs, such as Durvalumab (anti-PD-L1) and Tremelimumab (anti-CTLA-4) as rst-line therapy. This experiment included 1118 patients, and the median OS was 11.9 months (95% CI, 9.0-17.7) with Durvalumab plus Tremelimumab (HR vs. chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = 0.20).…”